WO2018218963A1 - 一种egfr抑制剂的药用盐及其晶型、制备方法和应用 - Google Patents

一种egfr抑制剂的药用盐及其晶型、制备方法和应用 Download PDF

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WO2018218963A1
WO2018218963A1 PCT/CN2018/070011 CN2018070011W WO2018218963A1 WO 2018218963 A1 WO2018218963 A1 WO 2018218963A1 CN 2018070011 W CN2018070011 W CN 2018070011W WO 2018218963 A1 WO2018218963 A1 WO 2018218963A1
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egfr inhibitor
pharmaceutically acceptable
acceptable salt
ray powder
powder diffraction
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PCT/CN2018/070011
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English (en)
French (fr)
Chinese (zh)
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周平
吴家权
金深霜
李莉
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无锡双良生物科技有限公司
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Priority to AU2018275277A priority Critical patent/AU2018275277B2/en
Priority to EP18810477.2A priority patent/EP3502113A4/en
Priority to US16/329,544 priority patent/US10759797B2/en
Priority to KR1020197006437A priority patent/KR102224789B1/ko
Priority to JP2019515244A priority patent/JP7146741B2/ja
Publication of WO2018218963A1 publication Critical patent/WO2018218963A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicine, and relates to a medicinal salt of an EGFR inhibitor and a crystal form thereof, a preparation method and application thereof.
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • some irreversible ATP competitive inhibitors such as HMPL-813, CI-1033, HKI-272, HS-10182, etc.
  • the structure of the irreversible inhibitor contains a receptor fragment which can undergo a Michael addition reaction, which is capable of generating a covalent bond with a thiol group (SH) in a conserved amino acid residue (Cys797) of the receptor binding site.
  • SH thiol group
  • Cys797 conserved amino acid residue
  • AstraZeneca's AZD9291 is the first third-generation oral, irreversible, selective EGFR mutation inhibitor for activated and resistant mutant EGFR, meaning that AZD9291 can be caused by T790M mutations. The resistance is not effective. AZD9291 has a better therapeutic effect on NSCLC patients who are resistant to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M mutation.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • Chinese Patent Application No. CN103702990A discloses the structure of the compound of AZD9291, and the application also discloses a polymorph of AZD9291 and its pharmaceutically acceptable form of the methanesulfonate.
  • Chinese invention patent application CN106132957A discloses a series of 2-arylaminopyridine, pyrimidine or triazine derivatives and is characterized by structure.
  • the application also tested the above compounds at the cellular level, and the results showed that these compounds have high EGFR inhibitory activity and relatively low inhibitory activity against wild-type EGFR, and thus can be developed into new antitumor drugs.
  • the above application lacks research and protection on the medicinal form of the drug substance (such as the salt crystal form) and needs further development and improvement.
  • the present invention provides a pharmaceutically acceptable salt of the EGFR inhibitor and Its crystal form, preparation method and application.
  • the present invention provides a pharmaceutically acceptable salt of an EGFR inhibitor which is a salt formed by an EGFR inhibitor and an acid, the EGFR inhibitor having a structure as shown in Formula I,
  • the acid is methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, hydrogen chloride or citric acid.
  • the pharmaceutically acceptable salt of the EGFR inhibitor wherein the mesylate salt has a crystal form A, and the X-ray powder diffraction pattern of the crystal form A has a 2 ⁇ value of 6.8° ⁇ 0.2°, 14.0° ⁇ 0.2°, 21.6°. There is a characteristic peak at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form A has a characteristic peak at at least one of 2 ⁇ values of 13.5° ⁇ 0.2°, 15.6° ⁇ 0.2°, 18.1° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A has a 2 ⁇ value of 5.8° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 17.5°. At least one of ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 22.2° ⁇ 0.2°, 24.6° ⁇ 0.2°, 27.2° ⁇ 0.2°, and 27.7° ⁇ 0.2° has characteristic peaks.
  • the pharmaceutically acceptable salt of the EGFR inhibitor has a crystalline form B of p-toluenesulfonate, and the X-ray powder diffraction pattern of the crystalline form B has a 2 ⁇ value of 10.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 18.1. Characteristic peaks are found at ° ⁇ 0.2°, 22.4° ⁇ 0.2°, and 24.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has a 2 ⁇ value of 7.8° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.9° ⁇ 0.2°, 18.7° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.4°. At least one of ⁇ 0.2°, 23.7° ⁇ 0.2° has a characteristic peak.
  • the X-ray powder diffraction pattern of the Form B is in the 2 ⁇ values of 11.2° ⁇ 0.2°, 11.7° ⁇ 0.2°, 14.2° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.5° ⁇ 0.2°, 19.7°. At least one of ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.3° ⁇ 0.2°, 26.9° ⁇ 0.2°, 28.0° ⁇ 0.2°, and 29.5° ⁇ 0.2° has characteristic peaks.
  • the pharmaceutically acceptable salt of the EGFR inhibitor wherein the phosphate has a crystal form C, and the X-ray powder diffraction pattern of the crystal form C has a 2 ⁇ value of 14.1 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, 25.3 ° ⁇ 0.2 There is a characteristic peak at °.
  • the X-ray powder diffraction pattern of the Form C has a characteristic peak at at least one of 2 ⁇ values of 8.9° ⁇ 0.2°, 19.9° ⁇ 0.2°, and 22.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form C is in the 2 ⁇ values of 11.2° ⁇ 0.2°, 11.9° ⁇ 0.2°, 12.6° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.8° ⁇ 0.2°, 20.5°. At least one of ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.2° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.5° ⁇ 0.2°, 26.0° ⁇ 0.2°, 28.2° ⁇ 0.2° Characteristic peaks.
  • the pharmaceutically acceptable salt of the EGFR inhibitor wherein the hydrochloride salt has a crystal form D, and the X-ray powder diffraction pattern of the crystal form D has a 2 ⁇ value of 7.8° ⁇ 0.2°, 9.8° ⁇ 0.2°, 16.2° ⁇ There are characteristic peaks at 0.2°, 21.3° ⁇ 0.2°, 26.3° ⁇ 0.2°, and 27.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form D has a 2 ⁇ value of 16.0° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.5° ⁇ 0.2°, 24.6°. At least one of ⁇ 0.2°, 25.8° ⁇ 0.2° has a characteristic peak.
  • the X-ray powder diffraction pattern of the crystal form D has a 2 ⁇ value of 13.8° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.7° ⁇ 0.2°, 20.5° ⁇ 0.2°, 23.5°. At least one of ⁇ 0.2° has a characteristic peak.
  • the pharmaceutically acceptable salt of the EGFR inhibitor wherein the citrate has a crystal form E, and the X-ray powder diffraction pattern of the crystal form E has a 2 ⁇ value of 5.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 21.2° ⁇ There is a characteristic peak at 0.2°.
  • the X-ray powder diffraction pattern of the Form E has a characteristic peak at at least one of 2 ⁇ values of 10.8° ⁇ 0.2°, 17.5° ⁇ 0.2°, 24.9° ⁇ 0.2°, and 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form E is at least one of 2 ⁇ values of 9.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.3° ⁇ 0.2°, 16.0° ⁇ 0.2°, and 20.4° ⁇ 0.2°. There are characteristic peaks.
  • the pharmaceutically acceptable salt of the EGFR inhibitor is an amorphous phosphate having an X-ray powder diffraction pattern characteristic peak as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form of the pharmaceutically acceptable salt of the EGFR inhibitor, which comprises
  • the EGFR inhibitor and the acid are formed into a salt in an alcohol solvent or water; and a ketone solvent is added to form a crystal form of the pharmaceutically acceptable salt of the EGFR inhibitor.
  • the alcohol solvent has 1 to 6 carbon atoms
  • the ketone solvent has 3 to 6 carbon atoms.
  • the invention also provides the use of the pharmaceutically acceptable salt of the EGFR inhibitor in the preparation of a medicament for treating cancer, preferably in the preparation of a medicament for treating non-small cell lung cancer.
  • the present invention also provides an amorphous EGFR inhibitor phosphate which is a salt formed by an EGFR inhibitor of the formula I and a phosphoric acid, having an X-ray powder diffraction pattern characteristic peak as shown in FIG. 7;
  • a committed EGFR inhibitor phosphate in the preparation of a medicament for the treatment of cancer, preferably in the preparation of a medicament for the treatment of non-small cell lung cancer.
  • the present invention provides an EGFR inhibitor (N-(2-((2-(dimethylamino)ethyl))(methyl)amino)-4-methoxy-5-((4-(1-methyl-)- Methanesulfonate, p-toluenesulfonate, phosphate, hydrochloride or 1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide)
  • Citrate based on a particular crystal form, these pharmaceutically acceptable salts have higher solubility and stability than the corresponding free base, and are more suitable for drug development to meet bioavailability and efficacy requirements.
  • the pharmaceutically acceptable salt of the EGFR inhibitor (mesylate, p-toluenesulfonate, phosphate, hydrochloride, citrate) provided by the present invention is sandy or compared to the free base form of the EGFR inhibitor. Granular, more convenient for the processing of subsequent preparations.
  • Figure 1 is an XRPD pattern of the EGFR inhibitor mesylate salt in the form of Form A;
  • Figure 2 is a DSC chart of the EGFR inhibitor mesylate salt in the form of Form A;
  • Figure 3 is an XRPD pattern of the EGFR inhibitor p-toluenesulfonate in the form of Form B;
  • Figure 4 is a DSC chart of the EGFR inhibitor p-toluenesulfonate in the form of Form B;
  • Figure 5 is an XRPD pattern of an EGFR inhibitor phosphate present in the form of Form C;
  • Figure 6 is a DSC chart of the EGFR inhibitor phosphate present in the form of Form C;
  • Figure 7 is an XRPD pattern of an EGFR inhibitor phosphate present in an amorphous form
  • Figure 8 is an XRPD pattern of the EGFR inhibitor hydrochloride in the form of Form D;
  • Figure 9 is a DSC chart of the EGFR inhibitor hydrochloride in the form of Form D;
  • Figure 10 is an XRPD pattern of the EGFR inhibitor citrate in the form of Form E;
  • Figure 11 is a DSC chart of the EGFR inhibitor citrate in the form of Form E;
  • Figure 12 is a graph showing the stability test results (XRPD comparison chart) of the EGFR inhibitor mesylate in the form of Form A, wherein the XRPD pattern of the sample at the start time is sampled from bottom to top, and the sample is at 40 ° C / 75 XRPD pattern measured after 1 month of placement under %RH conditions;
  • Figure 13 is a graph showing the stability test results of the EGFR inhibitor p-toluenesulfonate in the form of Form B (XRPD comparison chart), wherein the XRPD pattern of the sample at the start time is sampled from bottom to top, and the sample is at 40 ° C / XRPD pattern measured after being placed for 1 month under 75% RH conditions;
  • Figure 14 is a graph showing the stability test results (XRPD comparison chart) of the EGFR inhibitor phosphate present in the form of Form C, wherein the XRPD pattern of the sample at the start time is sampled from bottom to top, and the sample is at 40 ° C / 75% RH. The XRPD pattern measured after being placed for 1 month under the conditions;
  • Figure 15 is a graph showing the stability test results (XRPD comparison chart) of the EGFR inhibitor phosphate present in an amorphous form, wherein the XRPD pattern of the sample at the start time and the sample at 40 ° C / 75% RH are sequentially listed from bottom to top. The XRPD pattern measured after being placed for 1 month;
  • Figure 16 is a graph showing the stability test results (XRPD comparison chart) of the EGFR inhibitor hydrochloride in the form of Form D, wherein the XRPD pattern of the sample at the start time is determined from bottom to top, and the sample is at 40 ° C / 75%. XRPD pattern measured after being placed for 1 month under RH conditions;
  • Figure 17 is a graph showing the stability test results (XRPD comparison chart) of the EGFR inhibitor citrate in the form of Form E, wherein the XRPD pattern of the sample at the start time is determined from bottom to top, and the sample is at 40 ° C / 75%. XRPD pattern measured after being placed for 1 month under RH conditions;
  • Figure 18 is a 1 H-NMR chart of an EGFR inhibitor in the form of a free base
  • Figure 19 is a mass spectrum of an EGFR inhibitor in the form of a free base
  • Figure 20 is a 1 H-NMR chart of the EGFR inhibitor mesylate salt in the form of Form A;
  • Figure 21 is a 1 H-NMR chart of the EGFR inhibitor p-toluenesulfonate in the form of Form B;
  • Figure 22 is a 1 H-NMR chart of the EGFR inhibitor phosphate present in the form of Form C;
  • Figure 23 is a 1 H-NMR chart of the EGFR inhibitor hydrochloride in the form of Form D;
  • Figure 24 is a 1 H-NMR chart of the EGFR inhibitor citrate in the form of Form E.
  • the present invention provides a pharmaceutically acceptable salt of an EGFR inhibitor having the structural formula shown in Formula I (chemical name: N-(2-((2-(dimethylamino)ethyl)))) Amino)-4-methoxy-5-(4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-ylamino)phenyl)acrylamide) :
  • the pharmaceutically acceptable salt includes methanesulfonate, p-toluenesulfonate, phosphate, hydrochloride or citrate.
  • the EGFR inhibitors of the present invention all refer to the above compounds unless otherwise specified.
  • the invention further provides a crystalline form of a pharmaceutically acceptable salt of the EGFR inhibitor.
  • the crystal form is Form A.
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 5.8° ⁇ 0.2°, 6.8°. ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.0° ⁇ 0.2°, 13.5° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.8° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.5° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 18.6 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °, 24.6 ° ⁇ 0.2 °, 27.2 ° ⁇ 0.2 °, a characteristic peak at 27.7 ° ⁇ 0.2 °; further, the X-ray powder diffraction pattern of the crystalline form A is substantially identical to that of Figure 1;
  • the crystalline form is Form B.
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 7.8° ⁇ 0.2°, 10.2.
  • the crystalline form is Form C.
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 8.9 ° ⁇ 0.2 °, 11.2 ° ⁇ 0.2.
  • the crystalline form is Form D.
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 7.8° ⁇ 0.2°, 9.8 ° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.2° ⁇ 0.2° 20.5° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.5° ⁇ 0.2°, 24.6° ⁇ 0.2°, 25.8° ⁇ 0.2°, 26.3° ⁇ 0.2°, 27.6 a characteristic peak at ° ⁇ 0.2°; further, the X-ray powder diffraction pattern of the crystal form D is substantially identical to FIG. 8; further, the differential scanning calorimetry chart of the crystal form D is substantially identical to Figure 9 is consistent.
  • the crystal form is Form E
  • the X-ray powder diffraction pattern has a 2 ⁇ value of 5.4° ⁇ 0.2°, 9.0° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.0. ° ⁇ 0.2°, 12.4° ⁇ 0.2°, 13.3° ⁇ 0.2°, 16.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, 24.9° ⁇ 0.2°, 25.4° ⁇ a characteristic peak at 0.2°;
  • the X-ray powder diffraction pattern of the Form E is substantially identical to FIG. 10;
  • the differential scanning calorimetry diagram of the Form E is substantially the same as FIG. 11 Consistent.
  • the preparation method of the crystalline form of the pharmaceutically acceptable salt of the EGFR inhibitor comprises:
  • the EGFR inhibitor and the acid in the form of a free base are formed into a salt in an alcohol solvent or water, followed by addition (preferably dropwise addition) of a ketone solvent to obtain a crystalline form of the pharmaceutically acceptable salt of the EGFR inhibitor.
  • the EGFR inhibitor and acid present in the form of the free base preferably form a salt in equimolar amounts.
  • the alcohol solvent has a carbon number of 1 to 6; more preferably, the alcohol solvent is methanol or ethanol.
  • the ratio of the alcohol solvent to the EGFR inhibitor is 2 to 5 ml: 1 g, preferably 3 ml: 1 g.
  • the ketone solvent has a carbon number of 3 to 6; more preferably, the ketone solvent is acetone.
  • the ratio of the ketone solvent to the EGFR inhibitor is 10 to 30 ml: 1 g, preferably 20 ml: 1 g.
  • the preparation method of the EGFR inhibitor phosphate (amorphous) comprises: forming an EGFR inhibitor in the form of a free base with a phosphoric acid, and then adding a ketone solvent to precipitate a solid.
  • the EGFR inhibitor and phosphoric acid present in the form of the free base preferably form a salt in equimolar amounts.
  • the ketone solvent has a carbon number of 3 to 6; more preferably, the ketone solvent is acetone.
  • DSC differential scanning calorimetry
  • the EGFR inhibitor used in the following examples was self-made with a purity of 99.7%, and the apparent trait was a pale yellow granular solid.
  • the structure confirmation data is as follows:
  • Example 1 EGFR inhibitor mesylate (Form A).
  • EGFR inhibitor (12.0 g, 24 mmol) in the form of the free base was weighed at room temperature, placed in a 500 mL single-mouth bottle, and 36 mL of ethanol was added. Methanesulfonic acid (2.32 g, 24 mmol) was added and dissolved by stirring at 40 to 50 °C. Then, 240 mL of acetone was added dropwise, and the mixture was stirred at 0 to 5 ° C to precipitate a gray solid.
  • the filter cake was rinsed with a small amount of acetone, and dried at 60 ° C using a vacuum drying oven to obtain a light brown solid (10.1 g, purity 99.0%, moisture 0.97%, melting point 150.5 to 152.8 ° C).
  • the solid obtained in the present example was tested as an EGFR inhibitor mesylate salt, and its crystal form was named as crystal form A.
  • the XRPD data of the crystal form is shown in Table 1, and the XRPD pattern is shown in FIG. Figure 2 shows.
  • Example 2 EGFR inhibitor p-toluenesulfonate (Form B).
  • the solid obtained in the present example was tested to be an EGFR inhibitor p-toluenesulfonate, and its crystal form was named as Form B.
  • the XRPD data of the crystal form is shown in Table 2, and the XRPD pattern is shown in Figure 3. As shown in Figure 4.
  • An EGFR inhibitor (3.0 g, 6 mmol) in the form of the free base was weighed at room temperature, placed in a 250 mL single-mouth bottle, and 9 mL of ethanol was added.
  • An 85 wt% aqueous phosphoric acid solution (0.69 g, 6 mmol in terms of phosphoric acid) was added, and the mixture was stirred for 2 hours to dissolve.
  • 60 mL of acetone was added dropwise to precipitate a gray solid. After suction filtration, the filter cake was rinsed with a small amount of acetone and dried to give a brown solid (3.5 g, purity 97.9%, moisture 1.07%, melting point 182.5 to 184.8 ° C).
  • the solid obtained in the present example was tested as an EGFR inhibitor phosphate, and its crystal form was named as Form C.
  • the XRPD data of the crystal form is shown in Table 3, the XRPD pattern is shown in Figure 5, and the DSC chart is shown in Figure 6. Shown.
  • Example 4 EGFR inhibitor phosphate (amorphous).
  • the EGFR inhibitor (9.0 g, 18 mmol) in the form of the free base was weighed at room temperature, placed in a 500 mL single-mouth bottle, and 85 wt% aqueous phosphoric acid solution (2.08 g, 18 mmol in terms of phosphoric acid) was added at 40-50 ° C. Stir and dissolve. Then, 180 mL of acetone was added dropwise to precipitate a gray solid. After suction filtration, the filter cake was rinsed with a small amount of acetone and dried to give a pale gray solid (11.0 g, purity 98.5%).
  • the solid obtained in this example was tested to be an amorphous powder of the EGFR inhibitor phosphate, and its XRPD pattern is shown in FIG.
  • Example 5 EGFR inhibitor hydrochloride (Form D).
  • EGFR inhibitor (15.0 g, 30 mmol) in the form of the free base was weighed at room temperature, placed in a 500 mL single-mouth bottle, and concentrated hydrochloric acid (2.5 mL, 30 mmol in terms of hydrogen chloride) in ethanol (45 mL) was added to 40 Stir at ⁇ 50 °C. Then, 360 mL of acetone was added dropwise to precipitate a gray solid. After suction filtration, the filter cake was rinsed with a small amount of acetone and dried to give a brown solid (15 g, purity 99.2%, moisture 0.77%, melting point 250.5 ° C - 152.8 ° C).
  • the solid obtained in this example is an EGFR inhibitor hydrochloride, and its crystal form is named as crystal form D.
  • the XRPD data of the crystal form is shown in Table 4, the XRPD pattern is shown in FIG. 8, and the DSC chart is shown in FIG. 9 is shown.
  • Example 6 EGFR inhibitor citrate (Form E).
  • EGFR inhibitor (10.0 g, 20 mmol) in the form of the free base was weighed at room temperature, placed in a 500 mL single-mouth bottle, and 30 mL of ethanol was added. Citric acid monohydrate (4.2 g, 20 mmol) was added and dissolved by stirring at 40 to 50 °C. Then, 200 mL of acetone was added dropwise to precipitate a gray solid. After suction filtration, the filter cake was rinsed with a small amount of acetone and dried to give a light gray solid (11.3 g, purity 98.9%, moisture 0.97%, melting point 193.1 to 195.6 ° C).
  • the solid obtained in the present example is an EGFR inhibitor citrate, and its crystal form is named as crystal form E.
  • the XRPD data of the crystal form is shown in Table 5, the XRPD pattern is shown in FIG. 10, and the DSC chart is shown in FIG. 11 is shown.
  • Example 7 Crystalline wettability study.
  • a plurality of EGFR inhibitor pharmaceutically acceptable salts in the form of crystals in Examples 1-3 and 5-6, an amorphous EGFR inhibitor phosphate in Example 4, and an EGFR inhibitor in the form of a free base are cited.
  • the wet contrast study was carried out in accordance with the Chinese Pharmacopoeia 2015 edition four appendix 9103 method (temperature 25 ° C ⁇ 1 ° C, relative humidity 80% ⁇ 2%), the results are shown in Table 6.
  • the EGFR inhibitor in the form of the free base has a small wettability, the citrate crystal form E is comparable thereto, and the mesylate salt form A and the phosphate form C are larger than this.
  • Deliquescence absorbs enough water to form a liquid.
  • the wetting weight gain is not less than 15%.
  • the wetting weight gain is less than 15% but not less than 2%.
  • wetting gain is less than 0.2%.
  • Do dose index
  • Mo single highest dose of drug (refer to the relevant dose of Ochinib, tentatively set to 80mg)
  • Vo volume of body fluid required for drug dissolution (about 250ml);
  • Cs saturated solubility of the drug;
  • the water is used as a solvent, and the EGFR inhibitor mesylate, p-toluenesulfonate, phosphate, hydrochloride and citrate prepared in Examples 1 to 3 and 5 to 6 are weighed and made into a saturated amount.
  • the solution was sampled at 1 hour, 4 hours, and 24 hours after the placement, and the concentration of each sample at the time of saturation was calculated according to the linear equation. The results are shown in Table 8.
  • the EGFR inhibitor mesylate (crystal form A), p-toluenesulfonate (crystal form B), phosphate (crystal form C), and phosphoric acid prepared in Examples 1 to 6 were weighed using artificial gastric juice as a solvent. Salt (amorphous), hydrochloride (crystal form C) and citrate (crystal form E) were prepared in appropriate amounts and prepared as a saturated solution. Samples were taken at 1 hour, 4 hours, and 24 hours after placement, and calculated according to a linear equation. The concentration of each sample at the time of saturation was as shown in Table 9.
  • the EGFR inhibitors methanesulfonate, phosphate (crystal form C), phosphate (amorphous) and citrate have higher solubility in water and artificial gastric juice.
  • Example 11 Crystalline stability study.
  • the medicinal salts of the six EGFR inhibitors in Examples 1 to 6 were placed under the conditions of 40 ° C / 75% RH, and the accelerated stability study was carried out for one month, and each sample was taken at the end of 0 and 1 month, respectively.
  • the shape, purity and crystal form stability (XRPD pattern) the results are shown in Table 10, the stability results of the methanesulfonate crystal form A are shown in Figure 12, and the stability of the p-toluenesulfonate crystal form B The results are shown in Fig. 13.
  • the stability results of the phosphate crystal form C are shown in Fig. 14.
  • the stability results of the phosphate amorphous powder are shown in Fig. 15, and the stability result of the hydrochloride crystal form D is shown in Fig. 16.
  • the stability results of the citrate crystal form E are shown in FIG.
  • the pharmaceutically acceptable salt of the EGFR inhibitor of the present invention and its specific crystal form have excellent physical and chemical properties, and are more suitable for development into a drug, satisfying bioavailability and efficacy. Requirements.

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WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
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WO2020245208A1 (en) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of cd9 as a biomarker and as a biotarget in glomerulonephritis or glomerulosclerosis
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
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WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof

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